Journal of Reproductive Immunology 133 (2019) 1–6

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Journal of Reproductive Immunology

journal homepage: www.elsevier.com/locate/jri

Oral sex is associated with reduced incidence of recurrent miscarriage T

a,⁎ a b a c c,d
T. Meuleman , N. Baden , G.W. Haasnoot , M.M. Wagner , O.M. Dekkers , S. le Cessie ,
C. Picavete, J.M.M. van Litha, F.H.J. Claasb, K.W.M. Bloemenkampa,f
a
Department of Obstetrics, Leiden University Medical Centre, Leiden, the Netherlands
b
Department of Immunohematology and Blood transfusion, Leiden University Medical Centre, Leiden, the Netherlands
c
Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands
d
Medical Statistics, Department of Biomedical Datasciences, Leiden University Medical Centre, Leiden, the Netherlands
e
AllthatChas Research Consultancy, Amsterdam, the Netherlands
f
Department of Obstetrics, Wilhelmina Children Hospital Birth Centre, Division Woman and Baby, University Medical Centre Utrecht, Utrecht, the Netherlands

A R T I C LE I N FO A B S T R A C T

Keywords: A possible way of immunomodulation of the maternal immune system before pregnancy would be exposure to
Pregnancy complications paternal antigens via seminal fluid to oral mucosa. We hypothesized that women with recurrent miscarriage
Oral sex have had less oral sex compared to women with uneventful pregnancy.
Recurrent miscarriage In a matched case control study, 97 women with at least three unexplained consecutive miscarriages prior to
Seminal fluid
the 20th week of gestation with the same partner were included. Cases were younger than 36 years at time of the
Sexual behavior
third miscarriage. The control group included 137 matched women with an uneventful pregnancy. The asso-
ciation between oral sex and recurrent miscarriage was assessed with conditional logistic regression, odds ratios
(ORs) were estimated. Missing data were imputed using Imputation by Chained Equations.
In the matched analysis, 41 out of 72 women with recurrent miscarriage had have oral sex, whereas 70 out of
96 matched controls answered positive to this question (56.9% vs. 72.9%, OR 0.50 95%CI 0.25−0.97,
p = 0.04). After imputation of missing exposure data (51.7%), the association became weaker (OR 0.67, 95%CI
0.36–1.24, p = 0.21).
In conclusion, this study suggests a possible protective role of oral sex in the occurrence of recurrent mis-
carriage in a proportion of the cases. Future studies in women with recurrent miscarriage explained by immune
abnormalities should reveal whether oral exposure to seminal plasma indeed modifies the maternal immune
system, resulting in more live births.

1. Introduction
About 1% of all couples trying to conceive, are confronted with
recurrent miscarriage, which is often defined as three or more con-
secutive pregnancies losses prior to the 20th week of gestation (Coulam,
1991). Possible etiologic factors include uterine anomalies, endocrine
disorders, maternal inherited and acquired thrombophilia, and parental
chromosomal abnormalities (Branch et al., 2010; Larsen et al., 2013).
However, in only about 25–50% of the couples an underlying cause for
recurrent miscarriage can actually be identified (Rai and Regan, 2006;
Branch et al., 2010).
Most research into the immunology of recurrent miscarriage focused
on the maternal immune system, leaving paternal factors aside.
However, males seems to be capable to affect the female immune
system prior to conception (Robertson and Sharkey, 2001). Studies in
mice have shown that during copulation, thus before implantation,
fetus specific maternal tolerance toward paternal antigens is induced
(Moldenhauer et al., 2009).
A well-known route to induce immune tolerance is via oral ex-
posure, possibly because the gut has the most adequate absorption in
the absence of an inflammatory environment (Sosroseno, 1995;
Brandtzaeg, 1996). In transplantation models of rats, oral administra-
tion of MHC molecules diminishes the occurrence of allograft rejection
(Hancock et al., 1993). In addition, Clark et al showed that direct
seminal plasma antigen presentation to a mouse model of NK-cell
mediated recurrent miscarriage may prevent the rejection of embryos
(Clark et al., 2013).
Koelman et al hypothesized that a potent way of inducing tolerance
towards paternal HLA antigens of the fetus in pregnancy would be ex-
posure of these antigens to oral mucosa (Koelman et al., 2000). To

⁎
Corresponding author at: Department of Obstetrics, K-6-P35, PO Box 9600, 2300 RC, Leiden, the Netherlands.
E-mail address: t.meuleman@lumc.nl (T. Meuleman).

https://doi.org/10.1016/j.jri.2019.03.005
Received 31 July 2018; Received in revised form 7 March 2019; Accepted 25 March 2019
0165-0378/ © 2019 Elsevier B.V. All rights reserved.
T. Meuleman, et al.
support this theory, they showed that both oral sex and swallowing
sperm reduced the incidence of preeclampsia (Koelman et al., 2000).
Another study showed that the pattern of oral sex practice was similar
in 66 women with two miscarriages and a control population
(N = 110), but 44.5% women in the control group swallowed sperm
compared to 24.2% of the women with recurrent miscarriage (Mattar
et al., 2005). Here we describe the outcome of a matched case control
study to assess the effect of oral sex on the occurrence of recurrent
miscarriage in a well-characterized population.
2. Material and methods
2.1. Case group
From 433 women who visited the recurrent miscarriage clinic of the
department of Obstetrics and Reproductive Medicine at the Leiden
University Medical Centre (LUMC), a tertiary referral center in the
Netherlands, between 2000 and 2014, 273 women were eligible and
invited to participate in this study.
Eligible cases were women who had three or more consecutive
miscarriages prior to the 20th week of gestation with the same partner,
and who were younger than 36 years at time of their third consecutive
miscarriage. Women with known causes for miscarriage such as uterine
anomalies, parental chromosomal abnormalities, and anti-phospholipid
syndrome were not eligible. The clinical work-up and definition for
known causes is previously described (Meuleman et al., 2017). Women
with hereditary thrombophilia were not excluded because the evidence
that hereditary thrombophilia is associated with recurrent miscarriage
is only weak (Larsen et al., 2013; McNamee et al., 2012). Both women
with primary recurrent miscarriage (no history of live birth) and sec-
ondary recurrent miscarriage (1 live birth followed by consecutive
miscarriages) were eligible.
From the 273 eligible women, 100 eligible women were included
(Fig. 1). Baseline characteristics from the 100 included women and 173
eligible, but not included women of which most women were non-re-
sponders, is depicted in Supplementary Table 1.
2.2. Control group
As it is postulated that the primary pathogenesis of various preg-
nancy complications is the same within individuals (Moffett et al.,
2004), controls were women with no miscarriage and only un-
complicated pregnancy(ies), i.e. no history of pregnancy complications
such as pregnancy-induced hypertension, preeclampsia, Hemolysis
Elevated Liver enzymes and Low Platelets (HELLP) syndrome (all de-
fined according to the criteria of the International Society for the study
of Hypertension in Pregnancy (ISHHP)), preterm birth (24–37 weeks),
fetal growth restriction (birth weight below the 2.3th percentile for
gestational age and sex (Kloosterman, 1969)), and perinatal death (fetal
loss after 20 weeks of gestation till 7 days after birth).
In the Netherlands it is common practice that community midwives
are taking care of low-risk women (with no medical or obstetrical his-
tory) during pregnancy and child birth. The zip code of each woman
with recurrent miscarriage was used to contact the nearest midwifery
practice to control for the impact of socio-economic status (SES) and
urbanity in the current analyses. Women with the same zip code, the
same age (difference in birth date maximally 1 year), and of which the
time of first delivery was close to the time of the third miscarriage of the
matched exposed woman (maximum 6 months before or 6 months
after) were asked to participate. We contacted at least 3 controls per
case. Enrolment took place between 2012 and 2014. (Fig. 1)
2.3. Ethical approval
The protocol was approved by the Ethics committee of the LUMC
(P12-099) and all participants gave informed consent. The study was
2
Journal of Reproductive Immunology 133 (2019) 1–6
registered with the Dutch trial registry NTR3402 and is part of the
REMI (REcurrent MIscarriages) studies, which investigate causes and
consequences of recurrent miscarriages.
2.4. Dutch reference group
In order to make the study more robust we obtained another control
group, i.e, Dutch reference group in which participants were asked to
fill in a digital questionnaire about relationships and sexual behaviour
(de Graaf, 2012), for specific details about selection of participants:
Wijsen and de Haas (Wijsen and de Haas, 2012). In total 14.892 per-
sons, including men and women, were approached of which 4170
(28%) filled in the questionnaire completely. For our reference group
we selected, from a total of 2075 women, 1259 women in the fertile age
(between 16 and 50 years) with a heterosexual relationship.
2.5. Variables and definitions
All cases and controls were asked to participate by filling in a digital
questionnaire or on paper in case women had no access to internet
between 2012 and 2014. The questionnaire was made using ProMISe,
an internet based, application for the design, maintenance, and use of
data management projects. Data were entered and stored in a good
clinical practice approved database (ProMISe Database, https://www.
msbi.nl/promise/).
The questionnaire contained questions about personal character-
istics, general disease history, intoxications (smoking, alcohol, drugs),
use of medication at different time points, outcome and complications
of all pregnancies, neonatal characteristics, family disease history,
partner’s characteristics, and questions about their recent sexual be-
haviour. Information about medical history, use of medication, in-
toxications, and pregnancy outcome was cross-checked in obstetrical
records to overcome recall bias. The data of the obstetrical records were
used in case of discrepancies between the questionnaire and obstetrical
records. For the questions about sexual behaviour additional informed
consent was requested. The sexual behaviour part entailed questions
about recent (frequency of) oral sex, swallowing the ejaculate, length of
the relationship, and monthly sexual frequency. To investigate whether
vaginal exposure of sperm was different between cases and controls,
recent contraception methods including use of condom were asked for.
(Supplementary data, Appendix 1).
Maternal age was defined as age at third consecutive miscarriage for
cases or age at first pregnancy for controls. Socioeconomic status was
categorized into high, middle or low by using mean household income
levels of a neighborhood, which was determined with the first four
digits of the zip code, using data from the Netherlands Institute for
Social Research (SCP, 2006). Education was defined as whether or not
university level (college and university education together). Ethnicity
was based on country of birth of the woman and divided in 4 groups
according to the rules of the Central Bureau of Statistics of the Neth-
erlands. (CBS, 2013)
2.6. Sample size considerations
Sample size calculation was performed assuming that 40–50% of the
cases and 60–80% of the controls would have oral sex (Koelman et al.,
2000; Saftlas et al., 2014), leading to the following more precise as-
sumptions adapted for the matched design:
Combination 1: (18%): Cases and controls both don’t have oral sex
Combination 2: (15%): Cases have oral sex, controls don’t have.
Combination 3: (35%): Cases don’t have oral sex, controls have.
Combination 4 (32%): Cases and controls both have oral sex
This implies an odds-ratio on the event of 0.43 for oral sex vs. no
oral sex. A sample size of 186 women (93 exposed, 93 non-exposed)
was expected to provide sufficient power (two-sided alpha .05. power
80%), taking a 10% drop-out in consideration. We planned 1:1
T. Meuleman, et al. Journal of Reproductive Immunology 133 (2019) 1–6

Fig. 1. Flowchart of subjects.

case:control ratio, that is, one woman who had recurrent miscarriage did not complete these questions were also included in the imputation
matched to one control. On forehand we expected a lot of non-re- model. Ten imputed datasets were created.
sponders and therefore we contacted at least 3 controls per case. PASS
2008, Power Analysis and Sample Size Software (Hintze J., NCSS
3. Results
Kaysville USA) was used for the sample size calculation.
3.1. Baseline characteristics
2.7. Statistical analysis
In total, 97 women with recurrent miscarriage were included and
137 matched controls (Fig. 1). Table 1 shows the baseline character-
The association between oral sex and recurrent miscarriage was
istics of the study population.
studied with conditional logistic regression using a stratified Cox re-
In the case group, 63 women (64.9%) had primary recurrent mis-
gression and odds ratios (ORs) were estimated. Statistics were per-
carriage and 34 (35.1%) secondary recurrent miscarriage. A total of 65
formed using SPSS (Version 24.0, Inc., Chicago, IL, USA). A p-
women had 4 or more consecutive miscarriages (67.0%), and 39
value < 0.05 was considered statistically significant.
women (40.2%) had 5 or more miscarriages. A total of 6 (6.2%) cases
Of the 97 cases and 137 controls, 51.7% did not complete all the
had hereditary thrombophilia, i.e, factor V Leiden (n = 4), prothrombin
questions about sexual behaviour, including questions about oral sex.
gene mutation (n = 3), or antithrombin deficiency (n = 1). None had
We compared the cases and controls who did complete questionnaires
protein C or S deficiencies. Out of 97 cases, 70 had at least one live birth
to cases and controls who did not using chi-square tests or Fisher’s exact
after the consecutive miscarriages (72.2%).
tests or Mann Whitney U tests, whichever were appropriate. We re-
peated the analyses with missing exposure data imputed using
Imputation by Chained Equations. In the imputation models the case/ 3.2. Sexual behaviour
controls status oral sex, swallowing the ejaculate, relationship duration
at time of index pregnancy, sexual frequency, and condom use as Of the 97 cases, 46 cases (47.4%) and of the 137 controls, 75 con-
contraception, and the variables used for matching cases and controls trols (55.9%) did not complete all the questions about sexual behaviour.
(SES, urbanity, maternal age at time of index pregnancy) were in- In Table 2 characteristics are shown of women with completed and
cluded. In addition, variables that were significantly different between women with not-completed questionnaire. Cases who did not complete
cases who completed all questions on sexual behaviour and cases who the questions about sexual behaviour were significantly more often

3
T. Meuleman, et al. Journal of Reproductive Immunology 133 (2019) 1–6

Table 1
Baseline characteristics.
Cases with primary recurrent miscarriage Cases with secondary recurrent miscarriage (N = 34) Controls without miscarriage
(N = 63) (N = 137)

Maternal age at index pregnancy 29.0 (27.0-32.0) 31.0 (27.7-33.0) 30.0 (27.0-32.0)
(years;median[IQR])
Maternal age at time of questionnaire 35.0 (31.0-38.0) 35.5 (33.0-38.2) 36.0 (33.0-39.0)
(years;median[IQR])
BMI (median[IQR])a 23.2 (21.6-27.4) 23.4 (20.9-25.7) 23.1 (21.0-25.8)
Smoking at time of questionnaire 10 (15.9) 4 (12.1) 18 (13.2)
Use of alcohol at time of questionnaire 34 (54.0) 17 (50.0) 87 (64.4)
Ethnic origin
Native/Caucasian 59 (93.7) 27 (79.4) 130 (94.9)
Turkish/Moroccan 2 (3.2) 1 (2.9) 2 (1.5)
Antillean/Surinamese 1 (1.6) 1 (2.9) 1 (0.7)
Other non-Caucasian immigrants 1 (1.6) 5 (14.6) 4 (2.9)
University level education 35 (55.6) 12 (35.3) 82 (59.9)
Urbanity
Few 9 (14.3) 5 (14.7) 15 (10.9)
Strong to moderate 37 (58.7) 16 (47.1) 78 (56.9)
Very strong 17 (27.0) 13 (38.2) 44 (32.1)
SES
Lowest 25% (< 25%) 4 (6.3) 6 (17.6) 19 (13.9)
Median 50% (25-75%) 33 (52.4) 18 (52.9) 64 (46.7)
Highest 25% (> 75%) 26 (41.3) 10 (29.4) 54 (39.4)
Gravidity (median[IQR]) 5 (5-8) 7 (6-8) 2 (1-2)
Parity (median[IQR]) 1 (0-2) 2 (1-2) 2 (1-2)

Data are n (%) unless otherwise indicated, BMI; Body mass index, SES; Socioeconomic status, IQR; interquartile range.
a
1.7% missing values (1 of 97 cases with secondary recurrent miscarriage and 3 of 137 controls).

smokers (p = 0.02). No other statistical differences were observed. Due
to incomplete questionnaires on sexual behaviour matched analysis on
oral sex was performed with 72 cases matched with 96 controls.
In the matched analysis, 41 out of 72 women with recurrent mis-
carriage reported to have oral sex, compared to 70 out of 96 matched
controls (56.9% vs. 72.9%, OR 0.50 95%CI 0.25−0.97, p = 0.04)
(Table 3). From the 41 women with recurrent miscarriage who in-
dicated to have oral sex, 39 women filled in the question on swallowing
the sperm and 9 indicated to swallow sperm (23.1%). In controls 68/70
matched controls who indicated to have oral sex filled in this question

Table 2
Baseline characteristics of cases and controls with complete and incomplete information on sexual behaviour.
Cases Controls (N = 137)
(N = 97)

Incomplete questions about Complete P-value Incomplete questions about Complete P-value
sexual behavior question about sexual sexual behavior question about sexual
(n = 46) behavior (n = 75) behavior
(n = 51) (n = 62)
Maternal age at index pregnancy 30 (27-32.2) 30 (27-32) 0.82a 30 (27-32) 30 (27.7-31) 0.77
(years;median[IQR])
Maternal age at time of 35 (33-39) 34 (31-37) 0.12a 36 (33-39) 35 (32-39) 0.35
questionnaire
(years;median[IQR])
BMI (median[IQR])b 23.0 (21.5-25.7) 24 (21.0-27.1) 0.31a 23.1 (20.9-26.0) 23.1 (21.0-25.8) 1.00
Smoking at time of questionnaire 11 (23.9) 3 (6.0) 0.02 11 (14.9) 7 (11.3) 0.54
Use of alcohol at time of 25 (54.3) 26 (51.0) 0.74 51 (68.9) 36 (59.0) 0.23
questionnaire
Ethnic origin 0.19 0.73
Native/Caucasian 42 (91.3) 44 (86.3) 72 (96.0) 58 (93.5)
Turkish/Moroccan 1 (2.2) 2 (3.9) 1 (1.3) 1 (1.6)
Antillean/Surinamese 2 (4.3) 0 (0.0) 0 (0.0) 1 (1.6)
Other non-Caucasian immigrants 1 (2.2) 5 (9.8) 2 (2.7) 2 (3.2)
University level education 22 (47.8) 25 (49.0) 0.91 45 (60.0) 37 (59.7) 0.97
Urbanity 0.62 0.68
Few 8 (17.4) 6 (11.8) 7 (9.3) 8 (12.9)
Strong to moderate 23 (50.0) 30 (58.8) 42 (56.0) 36 (58.1)
Very strong 15 (32.6) 15 (29.4) 26 (34.7) 18 (29.0)
SES 0.13 0.73
Lowest 25% (< 25%) 7 (15.2) 3 (5.9) 12 (16.0) 7 (11.3)
Median 50% (25-75%) 26 (56.5) 25 (49.0) 34 (45.3) 30 (48.4)
Highest 25% (> 75%) 13 (28.3) 23 (45.1) 29 (38.7) 25 (40.3)
Gravidity (median[min-max]) 6 (5-8.2) 7 (5-8) 0.79a 2 (1-2) 2 (1-2) 0.81
Parity (median[min-max]) 1 (1-2) 2 (1-2) 0.36a 2 (1-2) 2 (1-2) 0.61

Data are n (%) unless otherwise indicated, BMI; Body mass index, SES; Socioeconomic status, IQR; interquartile range.
All χ² tests or Fisher’s exact tests except a Mann Whitney U test. b1.7% missing values (1 of 97 cases with incomplete questions and 3 of 137 controls with incomplete
questions).

4
T. Meuleman, et al.
Table 3
Oral sex in women with recurrent miscarriage.
Recurrent miscarriage
(N = 97)
Oral sexa 41/72 (56.9)
Relationship duration at time of index pregnancy (median [IQR])b 7 (4-9)
Sex frequency (median [IQR])c 8 (4-8)
Condom use as contraceptiond 7/56 (12.5)
Data are n (%), OR; odds ratio, CI; confidence interval, P; p-value.
a
17.5% missing values (20 of 97 cases and 21 of 137 controls), 10.6% lost by matching (5 of 97 cases and 20 of 137 controls).
b
26.0% missing values (21 of 97 cases and 40 of 137 controls), 13.6% lost by matching (13 of 97 cases and 19 of 137 controls).
c
32.4% missing values (29 of 97 cases and 47 of 137 controls), 18.3% lost by matching (16 of 97 cases and 27 of 137 controls).
d
30.3% missing values (26 of 97 cases and 45 of 137 controls), 16.2% lost by matching (15 of 97 cases and 23 of 137 controls).
and 10 controls (14.7%) swallowed sperm. No significant differences
were observed in the incidence of oral sex in women with primary re-
current miscarriage and secondary recurrent miscarriage (63.3% vs.
46.4%, p = 0.15).
Table 3 also shows results after missing values being imputed. The
association became weaker with a crude OR of 0.67 (95%CI 0.36–1.24,
p = 0.21).
Out of the 1259 women selected as Dutch reference group, 1206
women filled in the question on oral sex. From the 1206 women 1076
women stated to have oral sex (89.2%) compared to 44 out of 77
women with recurrent miscarriage who filled in this question (57.1%)
(OR 0.16, 95%CI 0.09−0.26, p < 0.001).
4. Discussion
This matched case control study suggests that women with recurrent
miscarriage had less oral sex compared to women with uneventful
pregnancy. This is in line with the hypothesis that the gut has the most
adequate absorption in the absence of an inflammatory environment
(Sosroseno, 1995; Brandtzaeg, 1996), and seminal fluid contains so-
luble HLA antigens which can already induce maternal immune toler-
ance towards inherited paternal antigens of the fetus before implanta-
tion.
The strength of this study is that a large homogenous well-char-
acterized case group of women with at least three consecutive un-
explained recurrent miscarriages less than 20 weeks of gestation with
the same partner was included. Furthermore, we compared our data in
women with recurrent miscarriage to a representative group of Dutch
women in the fertile age. In this reference group 89.2% of the women
stated to have oral sex, this percentage is comparable to research on
heterosexual behaviour in the USA, that showed that 83.5% of the
women between age 35 years and 44 years ever had oral sex (Leichliter
et al., 2007). In addition, in a recent study on oral and vaginal exposure
to the father’s seminal fluid in preeclampsia, 78.6% of controls subjects
had oral sex (Saftlas et al., 2014). In contrast, in our study this was only
56.9% of the women with recurrent miscarriage, suggesting indeed that
having less oral sex might be associated with pregnancy complications
such as recurrent miscarriage.
Although it is suggested that particularly the vaginal route of ex-
posure to paternal antigens is critical to successful pregnancy (Saftlas
et al., 2014), earlier findings suggest that oral exposure to paternal
antigens reduced the incidence of preeclampsia (Koelman et al., 2000),
which is in line with our findings in recurrent miscarriage. Seminal
fluid contains all types of immunoregulatory factors such as cytokines,
hormones and soluble HLA (sHLA) antigens (Politch et al., 2007) in-
cluding sHLA-G. sHLA-G appears to have an important role in creating
tolerance during pregnancy (Athanassakis et al., 1999; Pfeiffer et al.,
2000; Zidi et al., 2016), and sHLA-G in seminal fluid may affect the
maternal immune system before implantation of the embryo (Larsen
et al., 2011). The gut has the most adequate absorption in the absence
5
Journal of Reproductive Immunology 133 (2019) 1–6
No miscarriage OR (95% CI) P OR (95% CI) P
(N = 137)
Missing values not imputed With missing values imputed
70/96 (72.9) 0.50 (0.25-0.97) 0.04 0.67 (0.36-1.24) 0.21
7 (4-9.2) 0.94 (0.84-1.05) 0.30 0.97 (0.88-1.07) 0.56
4 (4-8) 1.07 (0.96-1.19) 0.18 1.03 (0.95-1.12) 0.41
15/69 (21.7) 0.59 (0.23-1.49) 0.27 0.82 (0.39-1.70) 0.60
of an inflammatory environment (Sosroseno, 1995; Brandtzaeg, 1996),
and therefore having oral sex before implantation of the semi-allo-
geneic fetus could be a potent way of inducing immune tolerance to the
paternal HLA antigens.
We were confronted with incomplete data from questionnaires,
especially missing data on sexual behaviour, which was our exposure of
interest. We tried to overcome this problem by imputation, a standard
statistical approach to deal with missing data (Schafer, 1999). How-
ever, valid imputation assumes missing at random, meaning that other
variables with complete information are completely accountable for the
missing data. However this missingness at random is an untestable as-
sumption, but may be valid in our study as comparing responders to
non-responders showed no significant difference, except for smoking.
However, missingness at random could still be dependent on variables
not included in this study. The observed negative association between
oral sex and recurrent miscarriage became smaller after imputation of
the missing data, and the confidence interval included the null effect.
When performing an unmatched analysis between cases and controls
using only complete matched pairs, results were similar to the matched
analysis, when performing an unmatched analysis using all cases and
controls, results were similar to the results of the imputed analysis (data
not shown). This shows that our results should be interpreted with
caution. Potential information bias should also be taken into account, as
misclassification may have occurred due to the use of questionnaires
and self-reported data, which is impossible to overcome. Importantly,
seminal fluid exposure is not commonly recognized as a potential factor
that could influence the occurrence of recurrent miscarriage, this will
likely not have influenced the way women filled in the questionnaire.
For this reason, information bias is not likely explanation for the ob-
served association.
Our study is limited by the fact that the questions about sexual
behaviour and contraception did not concern the period before the
index pregnancy. This might explain the discrepancy in frequency of
sexual intercourse between our study and others showing that limited
seminal exposure or the use of barrier methods before conception play a
role in the occurrence of pregnancy complications such as preeclampsia
(Klonoff-Cohen et al., 1989; Robillard and Hulsey, 1996; Kho et al.,
2009). In our study the frequency of sexual intercourse was similar for
women with recurrent miscarriage and controls. It is unknown how
sexual behaviour changes during the years in individuals and therefore
the questions about sexual behaviour might not reflect sexual behaviour
before the index pregnancy especially in the women with recurrent
miscarriage. By questioning sexual behaviour after the occurrence of
recurrent miscarriage, the question remains whether having recurrent
miscarriage affects sexual behaviour or sexual behaviour influence the
occurrence of recurrent miscarriage.
Another possible limitation is that couples with recurrent mis-
carriage who did not participate in this study had overall significantly
fewer children and fewer live births after they had recurrent mis-
carriages. However, this suggests that the observed effects are rather an
T. Meuleman, et al.
underestimation due to the fact that the group with worse outcome
amongst the recurrent miscarriage cases did not participate.
Despite the limitations of this study and the issues addressed, orally
exposure to seminal fluid seems to induce maternal tolerance to pa-
ternal antigens and therefore influence pregnancy outcome in a positive
way. Our results suggest an association between less oral sex and the
occurrence of recurrent miscarriage; this however needs confirmation
given the limitations of the present study.
Acknowledgements
The authors would like to thank R. Wolterbeek for his help with the
power analysis.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jri.2019.03.005.
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